1-Alkyl-4-(3-substitutedphenyl)piperidines

ABSTRACT

8-Substituted-2,6-methano-3-benzazocines of general structure I in which A is —CH 2 —OH, —CH 2 NH 2 , —NHSO 2 CH 3 ,  
                 
and Y is O, S or 
 
NOH are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.  
                 
8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are preferred.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT applicationUS01/45581, filed Oct. 31, 2001, and published in English on May 10,2002, as WO 02/36573. PCT US01/45581 claimed priority of U.S.provisional application 60/244,438, filed Oct. 31, 2000. The entiredisclosures of both are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to opioid receptor binding compounds containingcarboxamides, formamides, thiocarboxamides and hydroxyamidines.

The compounds are useful as analgesics, anesthetics, anti-diarrhealagents, anti-retroviral agents, anticonvulsants, antitussives,anti-cocaine, and anti-addiction medications.

BACKGROUND OF THE INVENTION

Opiates have been the subject of intense research since the isolation ofmorphine in 1805, and thousands of compounds having opiate oropiate-like activity have been identified. Many opioidreceptor-interactive compounds including those used for producinganalgesia (e.g., morphine) and those used for treating drug addiction(e.g., naltrexone and cyclazocine) in humans have limited utility due topoor oral bioavailability and a very rapid clearance rate from the body.This has been shown in many instances to be due to the presence of the8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known asbenzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] andthe corresponding 3-OH group in morphinanes (e.g., morphine).

The high polarity of these hydroxyl groups retards oral absorption ofthe parent molecules. Furthermore, the 8-(or 3-)OH group is prone tosulfonation and glucuronidation (Phase II metabolism), both of whichfacilitate rapid excretion of the active compounds, leading todisadvantageously short half-lives for the active compounds.Unfortunately, the uniform experience in the art of the past seventyyears has been that removal or replacement of the 8-(or 3-)OH group haslead to pharmacologically inactive compounds.

SUMMARY OF THE INVENTION

We have now found that the 8-(or 3-)hydroxyl group may be replaced by anumber of small, polar, neutral residues, such as carboxamide,thiocarboxamide, hydroxyamidine and formamide groups. Not only do thebenzomorphan, morphinan carboxamides have unexpectedly high affinity foropioid receptors, compounds containing these groups in place of OH arefar less susceptible to Phase II metabolism and are generally moreorally bioavailable. The compounds of the invention are therefore usefulas analgesics, anesthetics, anti-pruritics, anti-diarrheal agents,anticonvulsants, antitussives, anorexics and as treatments forhyperalgesia, drug addiction, respiratory depression, dyskinesia, pain(including neuropathic pain), irritable bowel syndrome andgastrointestinal motility disorders. Drug addiction, as used herein,includes alcohol and nicotine addiction. There is evidence in theliterature that the compounds may also be useful as anti-retroviralagents, immunosuppressants and antiinflammatories and for reducingischemic damage (and cardioprotection), for improving learning andmemory, and for treating urinary incontinence.

In one aspect, the invention relates to2,6-methano-3-benzazocine-8-carboxamides and2,6-methano-3-benzazocine-8-carboxylate esters of formula:

wherein

-   A is chosen from —CH₂-Z, —CN, —NHSO₂—(loweralkyl),-   Q is chosen from O, S and NR^(17;)-   Y is chosen from O, S, NR¹⁷ and NOH;-   Z is chosen from OH, SH, CN and NH₂;-   R¹ is chosen from hydrogen, lower alkoxy, phenyl and —NHR⁸; R² and    R^(2a) are both hydrogen or taken together R² and R^(2a) are ═O;-   R³ is chosen from hydrogen, lower alkyl, alkenyl, aryl,    heterocyclyl, benzyl and hydroxyalkyl;-   R⁴ is chosen from hydrogen, hydroxy, amino, lower alkoxy, C₁-C₂₀    alkyl and C₁-C₂₀ alkyl substituted with hydroxy or carbonyl;-   R⁵ is lower alkyl;-   R⁶ is lower alkyl;-   R⁷ is chosen from hydrogen and hydroxy; or together R⁴, R⁵, R⁶ and    R⁷ may form from one to three rings, said rings having optional    additional substitution;-   R⁸ is chosen from hydrogen, —OH, —NH₂ and —CH₂R¹⁵;-   R¹⁵ is chosen from hydrogen, alkyl, aryl, substituted aryl and alkyl    substituted with alkoxy, amino, alkylamino or dialkylamino;-   R¹⁶ is chosen from hydrogen and NH₂; and-   R¹⁷ is chosen from hydrogen, alkyl, aryl and benzyl;    with the provisos that, (1) when R² and R^(2a) are hydrogen, R³ is    hydrogen or cyclopropyl, R⁴ is hydroxy, and together R⁵, R⁶ and R⁷    form two rings substituted with a spirodioxolane, A cannot be    —COOCH₃ or NHSO₂CH₃; (2) when R² and R^(2a) are hydrogen, R³ is    hydrogen or cyclopropyl, R⁴ is hydroxy, and together R⁵, R⁶ and R⁷    form the ring system of oxymorphone and naltrexone, A cannot be    NHSO₂CH₃;    -   (3) when R², R²′, R⁴ and R⁷ are hydrogen, R³ is cyclopropyl and        R⁵ and R⁶ are methyl, A cannot be —NHC(O)H. The explicit        provisos exclude oxymorphone and naltrexone-3-sulfonamides,        which were disclosed as having no activity in vitro or in vivo        [McCurdy et al. Org. Lett. 2, 819-821 (2000)]; and cyclazocine        formamide, which was disclosed as an intermediate in a synthesis        in U.S. Pat. Nos. 3,957,793; 4,032,529 and 4,205,171.        Additionally, when A is —CN, R⁷ must be hydroxyl. When R⁴, R⁵,        R⁶ and R⁷ form from one to three rings, it is preferred that        none of the rings formed by R⁴, R⁵, R⁶ and R⁷ is aryl or        heteroaryl.

Subclasses of the foregoing structure include:

-   II. 2,6-methano-3-benzazocines of the structure shown above, in    which R⁴, R⁵, R⁶ and R⁷ do not form additional rings;-   III. morphinans in which R⁵ and R⁶ form one ring:-   IV. morphinans in which R⁵, R⁶ and R⁷ form two rings:-   V. morphinans wherein R⁴ and R¹¹ form an additional sixth ring,    which may be saturated or unsaturated (but not fully aromatic):    In addition to the major subclasses, there are compounds such as    which the person of skill recognizes as closely related to the major    subclasses, but which defy easy description in a common Markush    structure.

In another aspect, the invention relates to a method for preparing asecond compound that interacts with an opioid receptor when a firstcompound that interacts with an opioid receptor is known. When the firstcompound contains a phenolic hydroxyl, the method comprises convertingthe phenolic hydroxyl to a residue chosen from the group described asthe variable A above.

In another aspect, the invention relates to a method for decreasing therate of metabolism of a compound that interacts at an opioid receptor.When the first compound contains a phenolic hydroxyl, the methodcomprises converting the phenolic hydroxyl to a residue chosen from thegroup described as the variable A above.

In another aspect, the invention relates to methods for inhibiting,eliciting or enhancing responses mediated by an opioid receptorcomprising:

(a) providing a first compound that inhibits, elicits or enhances anopioid receptor response;

(b) preparing a second compound that interacts with an opioid receptorby converting a phenolic hydroxyl group on the first compound to aresidue described as A above; and

(c) bringing the second compound into contact with the opioid receptor.

In another aspect, the invention relates to a method for treating adisease by altering a response mediated by an opioid receptor. Themethod comprises bringing into contact with the opioid receptor acompound having the formula

wherein B represents the appropriate residue of a known compound offormula

and the known compound of that formula alters a response mediated by anopioid receptor.

In another aspect, the invention relates to processes for convertingopioid-binding phenols or phenols on a benzomorphan or morphinan to acarboxamide. The carboxamide conversion processes comprise either:

(a) reacting the phenol with a reagent to convert it to a groupdisplaceable by CN^(⊖);

(b) reacting that group with Zn(CN)₂ in the presence of a Pd(0) catalystto provide a nitrile; and

(c) hydrolyzing the nitrile to a carboxamide; or:

(a) reacting the phenol with a reagent to convert the phenol to atriflate;

(b) reacting the triflate with carbon monoxide and ammonia in thepresence of a Pd(II) salt and a Pd(0) catalyst to provide a carboxamide;or

(a) reacting the phenol with a reagent to convert the phenol to atriflate;

(b) reacting the triflate with carbon monoxide and hexamethyldisilazanein the presence of a Pd(II) salt and a Pd(0) catalyst to provide asilylated carboxamide precursor; and

(c) hydrolyzing the silylated carboxamide precursor to provide acarboxamide.

Similar processes convert phenols to amidines and thioamides by reactingthe foregoing nitrile with hydroxylamine to produce a hydroxyamidine orreacting the foregoing carboxamide with a pentavalent phosphorus-sulfurreagent to produce a thioamide. For the purpose of the invention an“opioid-binding phenol” is one that exhibits binding at an opioidreceptor below 25 nM.

DETAILED DESCRIPTION OF THE INVENTION

From many years of SAR studies, it is known that the hydroxyl ofmorphinans and benzomorphans interacts with a specific site in theopiate receptor. Previous exploration of the tolerance of this site forfunctional groups other than phenolic hydroxyls has almost uniformlyresulted in the complete or near-complete loss of opioid binding. Wehave now surprisingly found that the hydroxyl can be replaced with oneof several bioisosteres. Although a fairly wide range of primary andsecondary carboxamides, as well as carboxylates, aminomethyl,hydroxymethyl and even dihydroimidazolyl exhibit binding in the desiredrange below 25 nanomolar, optimal activity is observed with acarboxamido, thiocarboxamido, hydroxyamidino or formamido group.

Since the hydroxyl functionality of benzomorphans and morphinans can bechemically converted to an amide by a simple, flexible and convenientroute described below, and since thiocarboxamido, hydroxyamidino andformamido compounds are also easily synthesized as described below, thedoor is opened to improving the bioavailability of virtually any of theknown and new therapeutic agents that rely on opioid binding for theiractivity. Moreover, since the receptor seems to tolerate some variationbeyond the α-carbon of A, one may contemplate further modulatingreceptor specificity, affinity and tissue distribution by varying theproperties of the alkyl or aryl substituents on A. Preferred residues Aare —COOCH₃, —COOEt, —CONH₂, —C(═S)NH₂, —C(O)NHOH, —C(O)NHNH₂, —CONHCH₃,—CONHBn, —CONHCH₂(4-MeOC₆H₄), 2-(4,5-dihydroimidazolyl), —C(═NOH)NH₂,—CH₂NH₂, CH₂OH, —COC₆H₅, —C(═NOH)C₆H₅, —NHCHO, —NHCHS and —NHSO₂CH₃.When R⁷ is hydroxyl, A may also be —CN. Most preferred are —CONH₂,—C(═S)NH₂, —C(═NOH)NH₂, and —NHCHO.

It is known in the art that compounds that are μ, δ and κ agonistsexhibit analgesic activity; compounds that are selective μ agonistsexhibit anti-diarrheal activity and are useful in treating dyskinesia; μantagonists and κ agonists are useful in treating heroin, cocaine,alcohol and nicotine addiction; κ agonists are also anti-pruritic agentsand are useful in treating hyperalgesia. Recently it has been found[Peterson et al. Biochem. Pharmacol. 61, 1141-1151 (2001)] that κagonists are also useful in treating retroviral infections. In general,the dextrorotatory isomers of morphinans of type III above are useful asantitussives and anticonvulsants. Additional diseases and conditions forwhich opioid agonists and antagonists are known to be useful includeirritable bowel syndrome, gastrointestinal motility disorder, obesityand respiratory depression. Certain opioids (e.g. fentanyl andderivatives) are useful as anesthetics, i.e. they alter the state ofconsciousness.

Opioid receptor ligands having known high affinity are shown in thefollowing charts 1 and 2. Replacement of OH in these compounds producescompounds that exhibit similar activity and better bioavailability.

Other opioid receptor ligands are described in Aldrich, J. V.“Analgesics” in Burger's Medicinal Chemistry and Drug Discovery, M. E.Wolff ed., John Wiley & Sons 1996, pages 321-44, the disclosures ofwhich are incorporated herein by reference.

We have examined the opioid receptor binding of a series of analogs ofknown compounds that interact at opioid receptors in which the OH isreplaced by the R-group shown in Tables 1-4. The standards are shown inTable 5. The affinities of the compounds of the invention weredetermined in guinea pig brain cells by the method described in Wentlandet al. Biorgan. Med. Chem. Lett. 9. 183-187 (2000). Alternatively, wherenoted, the affinities of the compounds of the invention were determinedin cloned human receptors in Chinese hamster ovary cells by the methoddescribed by Xu et al [Synapse 39, 64-69 (2001)]. CHO cell membranes,expressing the human μ, δ, or κ opioid receptor, were incubated with 12different concentrations of the compounds in the presence ofreceptor-specific radioligands at 25° C., in a final volume of 1 ml of50 mM Tris-HCl, pH 7.5. Nonspecific binding was determined using 1 μMnaloxone. Data are the mean value ±S.E.M from three experiments,performed in triplicate. TABLE 1 Cyclazocine subseries

[³H] [³H] [³H] DAMGO Naltrindole U69,593 example A = (μ) (δ) (κ)  1 CN540 ± 50  2700 ± 1400 71 ± 13  2 COOH  58 ± 1.8 320 ± 14    31 ± 0.87  3CO₂CH₃   45 ± 0.92  59 ± 2.1  2.0 ± 0.21  4 CONH₂ 0.41 ± 0.07  8.3 ±0.49 0.53 ± 0.06  4 CONH₂ 0.32 ± 0.04 NT 0.60 ± 0.04  4 CONH₂ · HCl 0.34± 0.01  4.9 ± 0.80 0.42 ± 0.02 4a (−)CONH₂ 0.17 ± 0.04 2.6 ± 0.6 0.28 ±0.01 4b (+)CONH₂  63 ± 5.4 570 ± 50   67 ± 1.6  5 C(═S)NH₂ 0.22 ± 0.02 4.0 ± 0.48 0.67 ± 0.01  6 CONHOH   12 ± 0.32 210 ± 40   6.9 ± 0.61  7CONHNH₂  60 ± 9.3 450 ± 62   19 ± 1.4  8 CONHCH₃  24 ± 1.6  63 ± 4.1 2.6 ± 0.19  9 CONHCH₂C₆H₅  20 ± 2.2 140 ± 18   78 ± 7.6 10CONHCH₂(4-MeOC₆H₄)  19 ± 1.5 150 ± 17  110 ± 3.1  11 CONHCH₂CH₂N(CH₃)₂ 26 ± 2.9 350 ± 51  44 ± 11 12 CONH(CH₂)₃N(CH₃)₂ 370 ± 54  3000 ± 230 310 ± 64  13 2-(4,5-H₂)-imidazolyl  23 ± 1.9  55 ± 5.1   11 ± 0.69 14C(═NOH)NH₂  3.8 ± 0.42   16 ± 0.67 0.90 ± 0.15 15 CH₂NH₂  31 ± 5.4 390 ±47   17 ± 2.9 16 CH₂OH  21 ± 2.0 210 ± 29   7.6 ± 0.80 17 COC₆H₅   33 ±0.90 490 ± 43   19 ± 2.6 18 C(═NOH)C₆H₅  86 ± 3.8 180 ± 15   7.2 ± 0.4038 CH₂CN  3.3 ± 1.5^(a) 2000 ± 685^(a )   2.9 ± 0.36^(a) 39 CH(N═OH)  18 ± 1.8^(a) 140 ± 15^(a )  0.73 ± 0.03^(a) 19 NHCHO  1.9 ± 0.14  37 ±3.9  0.85 ± 0.080 19a (−)NHCHO  1.1 ± 0.04  9.8 ± 0.28  0.49 ± 0.012 19b(+)NHCHO 2300 ± 160  >10,000 900 ± 8.7  20 NHCHS 0.76 ± 0.09   16 ± 0.300.63 ± 0.15 21 NHSO₂CH₃  15 ± 1.2 780 ± 170  21 ± 1.5 36 NHCONH₂   20 ±0.66 90 ± 12  15 ± 1.4 37 NHCSNH₂   10 ± 1.7^(a) 440 ± 72^(a )   4.0 ±0.54^(a)^(a)data from chinese hamster ovary rather than guinea pig brain

TABLE 2 Keto subseries:

[³H]DAMGO [³H]Naltrindole [³H]U69,593 example A = (μ) (δ) (κ) 22 CN (KC)680 ± 61  3400 ± 410    59 ± 0.77 23 CONH₂ (KC)  1.4 ± 0.07  20 ± 2.3 1.8 ± 0.10 24 CONH₂ (EKC)  1.2 ± 0.12  9.8 ± 0.50 0.70 ± 0.08 40 NHCHO 6.1 ± 0.83  52 ± 3.4  1.2 ± 0.11 (EKC)

TABLE 3 Merz subseries

[³H]DAMGO [³H]Naltrindole [³H]U69,593 example A = (μ) (δ) (κ) 25(-)-(2″S)-8-OH 0.19 ± 0.01  3.6 ± 0.40 0.09 ± 0.01 26 (-)-(2″S)-8-CONH₂0.052 ± 0.013  2.0 ± 0.15 0.089 ± 0.004 27 (-)-(2″R)-8-OH  4.0 ± 0.54 67 ± 4.3  1.5 ± 0.07 28 (-)-(2″R)-8-CONH₂  2.9 ± 0.17   34 ± 0.10  2.8± 0.24 29 (-)-(2″S)-8-CH₂NH₂  28 ± 2.3 300 ± 27   18 ± 1.9

TABLE 4 Other Series

[³H]DAMGO [³H]Naltrindol [³H]U69,593 example A = (μ) e (δ) (κ) 30 CONH₂(morphine)  34 ± 1.8 1900 ± 81  2000 ± 97  31 CONHCH₃ (morphine) 440 ±9.2  >10,000 >10,000 32 CONH₂ (naltrexone)  1.9 ± 0.21 110 ± 8.1    22 ±0.85 33 CO₂Et (naltrexone)  24 ± 1.7 970 ± 155   16 ± 0.70 41 (−) NHCHO(naltrexone)   4.1 ± 0.40^(a)  280 ± 7.6^(a)   2.3 ± 0.044^(a) 34 CONH₂(naltrindole)  47 ± 2.7 0.33 ± 0.04  99 ± 7.9 35 CONH₂ (buprenorphine) 2.3 ± 0.29  7.3 ± 0.61  4.3 ± 0.05 42 CONH₂ (nalbuphine)   3.8 ±0.62^(a) 150 ± 82^(a )  0.46 ± 0.04^(a) 43 CN (7-OH)   0.35 ± 0.092^(a) 82 ± 24^(a)   2.6 ± 0.21^(a) 44 CONH₂ (butorphanol)   0.15 ± 0.019^(a)  14 ± 2.1^(a)   0.39 ± 0.057^(a)

TABLE 5 Standards [³H]DAMGO [³H]Naltrindole [³H]U69,593 (μ) (δ) (κ)(±)-Cyclazocine 0.32 ± 0.02   1.1 ± 0.04  0.18 ± 0.020 (±)-Cyclazocine0.16 ± 0.01 ^(a)   2.0 ± 0.22 ^(a)  0.07 ± 0.01 ^(a) (+)-Cyclazocine 360 ± 16 1100 ± 63   76 ± 8.2 (−)-Cyclazocine 0.10 ± 0.03  0.58 ± 0.060.052 ± 0.009 (±)-EKC 0.78 ± 0.10   3.4 ± 0.41  0.62 ± 0.11(±)-ketocyclazocine  3.3 ± 0.66  20 ± 2.7  1.0 ± 0.24(±)-ketocyclazocine  1.7 ± 0.21 ^(a)  130 ± 14 ^(a)  1.0 ± 0.019 ^(a)naltrexone (3-OH) 0.17 ± 0.03  11 ± 1.1  0.31 ± 0.03 naltrindole (3-OH)  13 ± 1.1  0.13 ± 0.02  4.6 ± 0.23 buprenorphine 0.98 ± 0.11  0.72 ±0.10  0.90 ± 0.11 nalbuphine  1.6 ± 0.37 ^(a)  580 ± 80 ^(a)  3.0 ± 0.63^(a) butorphanol 0.12 ± 0.058 ^(a)  12 ± 3.8 ^(a)  0.22 ± 0.023 ^(a)Example 4 was tested several times independently to confirm the K_(i)'s.Inspection of the results in Table 1 indicates not only that affinity ispreserved in the compounds of the invention, but also that receptorselectivity can be modulated.

Antinociceptive activity is evaluated by the method described in Jianget al [J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page 1022].Compound 4 was found to exhibit an ED₅₀ of 0.21 nmol in the mouse aceticacid writhing test when administered i.c.v. Its “parent” cyclazocineexhibited an ED₅₀ of 2.9 nmol i.c.v. The time courses in producingantinociception in the mouse writhing test were compared for compound 4and cyclazocine. Mice were injected with 1.0 mg/kg of either compound 4or cyclazocine, given by i.p. administration. An increase in theduration of action from ca. 2 hr to 15 hr was observed for compound 4compared to cyclazocine.

Definitions

Throughout this specification the terms and substituents retain theirdefinitions.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s-and t-butyl,cyclobutyl and the like. Preferred alkyl groups are those of C₂₀ orbelow. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbongroups of from 3 to 8 carbon atoms. Examples of cycloalkyl groupsinclude c-propyl, c-butyl, c-pentyl, norbornyl and the like.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. Heteroaryl refers to any maximally unsaturatedheterocycle. The aromatic 6- to 14-membered carbocyclic rings include,e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to10-membered aromatic heterocyclic rings include, e.g., pyrrole,imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan,benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl, phenethyl and the like. Heteroarylalkyl means an alkyl residueattached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl,pyrimidinylethyl and the like.

Heterocycle means a cycloalkyl or aryl residue in which one to two ofthe carbons is replaced by a heteroatom such as oxygen, nitrogen orsulfur. Heteroaryls form a subset of heterocycles. Examples ofheterocycles that fall within the scope of the invention includepyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline,tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonlyreferred to as methylenedioxyphenyl, when occurring as a substituent),tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine,thiophene, furan, oxazole, oxazoline, isoxazole, dioxane,tetrahydrofuran and the like.

Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with halogen, hydroxy, loweralkoxy, carboxy,carboalkoxy, carboxamido, cyano, carbonyl, —NO₂, —NR¹R²; alkylthio,sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl,phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl,heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

Virtually all of the compounds described herein contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—. The present invention is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. In general it has been found that the levo isomerof morphinans and benzomorphans is the more potent antinociceptiveagent, while the dextro isomer may be useful as an antitussive orantispasmodic agent. Optically active (R)— and (S)— isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

Abbreviations

The following abbreviations and terms have the indicated meaningsthroughout:

-   Ac=acetyl-   BNB=4-bromomethyl-3-nitrobenzoic acid-   Boc=t-butyloxy carbonyl-   Bu=butyl-   c-=cyclo-   DAMGO=Tyr-ala-Gly-NMePhe-NHCH₂OH-   DBU=diazabicyclo[5.4.0]undec-7-ene-   DCM=dichloromethane=methylene chloride=CH₂Cl₂-   DEAD=diethyl azodicarboxylate-   DIC=diisopropylcarbodiimide-   DIEA=N,N-diisopropylethyl amine-   DMAP=4-N,N-dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   DPPF=1,1′-bis(diphenylphosphino)ferrocene-   DVB=1,4-divinylbenzene-   EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline-   Fmoc=9-fluorenylmethoxycarbonyl-   GC=gas chromatography-   HATU=O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HOAc=acetic acid-   HOBt=hydroxybenzotriazole-   Me=methyl-   mesyl=methanesulfonyl-   MTBE=methyl t-butyl ether-   NMO=N-methylmorpholine oxide-   PEG=polyethylene glycol-   Ph=phenyl-   PhOH=phenol-   Pfp=pentafluorophenol-   PPTS=pyridinium p-toluenesulfonate-   PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate-   rt=room temperature-   sat'd=saturated-   s-=secondary-   t-=tertiary-   TBDMS=t-butyldimethylsilyl-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TMOF=trimethyl orthoformate-   TMS=trimethylsilyl-   tosyl=p-toluenesulfonyl-   Trt=triphenylmethyl-   U69,593=

In the general processes described below, the preferred reagent toconvert a phenol to a group displaceable by CNW istrifluoromethansulfonic anhydride, which is usually employed in thepresence of base. Other reagents are known to persons of skill in theart to convert phenols to groups that may be displaced by cyanide anion.The advantage of the trifluoromethansulfonic anhydride procedure is thatit allows displacement under conditions that are mild enough to avoiddestruction of the rest of the molecule for most species of interest.Other reagents are operable, but require more robust substrates than maybe of interest in a particular case. The consideration of which to useis within the skill of the artisan. A preferred Pd(0) catalyst for usein the displacement with zinc cyanide istetrakis(triphenylphosphine)palladium. In the direct displacements withcarbon monoxide and ammonia or an ammonia equivalent, the preferredPd(0) catalyst is generated in situ from Pd(OAc)₂ or PdCl₂ and1,1′-bis(diphenylphosphino)-ferrocene. Other Pd(0) ligands include DPPF,DPPP, triphenylphosphine, 1,3-bis(diphenylphosphino)propane, BINAP andxantphos. The preferred pentavalent phosphorus-sulfur reagents forconverting carboxamides to thiocarboxamides are Lawesson's reagent andphosphorus pentasulfide.

It may happen that residues in the substrate of interest requireprotection and deprotection during the conversion of the phenol to thedesired bioisostere. Terminology related to “protecting”, “deprotecting”and “protected” functionalities occurs throughout this application. Suchterminology is well understood by persons of skill in the art and isused in the context of processes which involve sequential treatment witha series of reagents. In that context, a protecting group refers to agroup which is used to mask a functionality during a process step inwhich it would otherwise react, but in which reaction is undesirable.The protecting group prevents reaction at that step, but may besubsequently removed to expose the original functionality. The removalor “deprotection” occurs after the completion of the reaction orreactions in which the functionality would interfere. Thus, when asequence of reagents is specified, as it is in the processes of theinvention, the person of ordinary skill can readily envision thosegroups that would be suitable as “protecting groups”. Suitable groupsfor that purpose are discussed in standard textbooks in the field ofchemistry, such as Protective Groups in Organic Synthesis by T. W.Greene [John Wiley & Sons, New York, 1991], which is incorporated hereinby reference.

The compounds of the invention are synthesized by one of the routesdescribed below:

Chemical Syntheses

Proton NMR [Varian Unity-500 (500 MHz) NMR] data, direct insertion probe(DIP) chemical ionization mass spectra (Shimadzu GC-17A GC-MS massspectrometer), and infrared spectra (Perkin-Elmer Paragon 1000 FT-IRspectrophotometer) were consistent with the assigned structures of alltest compounds and intermediates. ¹H NMR multiplicity data are denotedby s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),and br (broad). Coupling constants are in hertz. Carbon, hydrogen, andnitrogen elemental analyses for all novel targets were performed byQuantitative Technologies Inc., Whitehouse, N.J., and were within −0.4%of theoretical values except as noted; the presence of water wasconformed by proton NMR. Melting points were determined on a Meltempcapillary melting point apparatus and are uncorrected. Optical rotationdata were obtained from a Perkin-Elmer 241 polarimeter. Reactions weregenerally performed under a N₂ atmosphere. Amines used in thePd-catalyzed amination reactions andracemic-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (BINAP) werepurchased from Aldrich Chemical Company and used as received unlessotherwise indicated. Tris(dibenzylideneacetone)dipalladium (0)[Pd₂(dba)₃], Pd(OAc)₂ 1,1′-bis(diphenylphosphino)ferrocene (DPPF), werepurchased from Strem Chemicals, Incorporated. Toluene and Et₂O weredistilled from sodium metal. THF was distilled from sodium/benzophenoneketyl. Pyridine was distilled from KOH. Methylene chloride was distilledfrom CaH₂. DMF and DMSO were distilled from CaH₂ under reduced pressure.Methanol was dried over 3 Å molecular sieves prior to use. Silica gel(Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used forflash column chromatography.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carbonitrile[1]. Thetriflate [36]of cyclazocine [35] ( 470 mg, 1.166 mmol), obtainedby the method of Wentland et al[Bioorian. Med. Chem. Lett. 9,183-187(2000)], was dissolved in 20 mL DMF and Zn(CN)₂ (272.6 mg, 2.322 mmol)and Pd(PPh₃)₄(53.9 mg, 0.0466 mmol) were added. After heating in 120° C.for 2 h, the reaction was allowed to stir at 25° C. overnight. A mixtureof EtOAc and NaHCO₃ solution was then added. The organic phase waswashed with brine and then dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to dryness. Flash column chromatography gave 1 asa colorless oil (260 mg, 80%). ¹H-NMR (500 MHz, CDCl₃) d 7.52 (b, 1H),7.37 (dd, J=7.8, 1.5 Hz, 1H), 7.14 (d, J=8.1, 1H), 3.15 (m, 1H), 2.96(d, J=19.0 Hz, 1H), 2.66-2.74 (m, 2H), 2.45 (m, 1H), 2.30 (m, 1H),1.84-1.98 (m, 3H), 1.38 (s, 3H), 1.29 (m, 1H), 0.85 (m, 1H), 0.82 (d,J=7.1 Hz, 3H), 0.51 (m, 2H), 0.10 (m, 2H). IR (film) 2961, 2918, 2225cm⁻. CI-MS, m/z (relative intensity) 281 (N+1, 100%). Anal. Calcd. forC₁₉H₂₄N₂.0.125H₂O: C, 80.78; H, 8.59; N, 9.92. Found: C 80.75; H 8.63; N9.89.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamide[4]. Compound 1 (80 mg, 0.286 mmol) was dissolved in about 1 mL t-butylalcohol. KOH (58.8 mg, 1.05 mmol) was then added. The reaction mixturewas stirred at reflux for about 20 min and the solvent was evaporatedand CH₂Cl₂ and MeOH and NaCl solution were added. The organic phase waswashed with brine and then dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to dryness to give 4 as white foam (80 mg, 95%).¹H-NMR

Mfz, CD₃OD) d 7.81 (m, 1H), 7.62 (m, 1H), 7.17 (m, 1H), 3.22 (m, 1H),3.04 (m, 1H), 2.66-2.82 (m, 2H), 2.50 (m, 1H), 2.35 (m, 1H), 1.86-1.98(m, 3H), 1.34 (s, 3H), 1.36 (m, 1H), 0.88 (m, 1H), 0.84 (d, J=7.0 Hz,3H), 0.54 (m, 2H), 0.16 (m, 2H). ¹³C-NMR (500 MHz, CD₃OD) d 172.71,143.32, 142.34, 133.01, 128.61, 126.61, 126.18, 60.67, 58.09, 46.92,42.74, 42.38, 37.69, 25.92, 25.07, 14.62, 9.67, 4.64, 4.52. IR (film)1654.2 cm⁻¹. CI-MS, m/z (relative intensity) 299 (M+1, 100%). Anal.Calcd: for C₁₉H₂₆N₂O.0.25H₂O: C 75.37; H 8.76; N 9.26. Found: C 75.27; H9.02; N 9.03.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,1-dimethyl-2,6-methano-3-benzazocin-8-carboxamide[1] (alternate procedure). A flask containing triflate 36 (100 mg),Pd(OAc)₂ (10.2 mg), and 1,1′-bis(diphenyl-phosphino)ferrocene(DPPF, 25mg) was purged with argon. The argon was replaced with gaseous CO andthe reaction vessel was closed to the atmosphere. Dry DMSO (1.25 mL) wasadded via syringe and gaseous ammonia was added to the resulting mixturevia a canula. A balloon was used to keep the additional volumecontained. The mixture was stirred for 17 h at 70° C. followed bycooling to 25° C. The reaction mixture was diluted with water and theproduct was extracted into ethyl acetate. The organic extracts waswashed with aqueous NaHCO₃ and dried (Na₂SO₄). Concentration of thesolvent in vacuo gave 90 mg of a crude product. This material waspurified via flash chromatography (25:1:0.1-CH₂Cl₂:MeOH: conc NH₄OH) toprovide 47 mg (65.3%) of compound 4.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxylicacid methyl ester [3]. A modification of a known procedure (Cacchi, S.;Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1986, 27,3931-3934) was used in this preparation. Under an argon atmosphere,triethylamine (0.30 mL, 2.15 mmol) was added to a mixture of the8-triflate ester of cyclazocine [36] (0.403 g, 1.0 mmol), palladiumacetate (0.0068 g, 0.03 mmol), 1,1′-bis(diphenylphosphino)ferrocene(0.00166 g, 0.03 mmol) and methanol (1 mL, 22.2 mmol) in DMF (1 mL). Thesolution was purged with carbon monoxide for 15 min and stirred under aCO balloon at 70° C. for 5 h. The reaction mixture was taken up in 20 mLof ethyl acetate and washed with saturated sodium bicarbonate solutionand water. The organic phase was dried with sodium sulfate andevaporated to give crude product as a brown oil. Chromatography onsilica gel using CH₂Cl₂:MeOH:NH₄OH (conc)/40:1:0.1 provided the desiredcompound 3 (0.235 g, 86.6%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃)δ 7.93 (d, J=1.7 Hz, 1H), 7.76 (dd, J₁=1.7 Hz, J₂=7.8 Hz, 1H), 7.12 (d,J=7.8 Hz, 1H), 3.89 (s, 3H), 3.15 (m, 1H), 2.96 (d, J=19.0 Hz, 1H), 2.73(d, J=6.1 Hz, 1H), 2.70 (m, 1H), 2.46 (dd, J₁=7.3 Hz, J₂=12.4 Hz, 1H),2.31 (dd, J₁=6.6 Hz, J₂=12.4 Hz, 1H), 1.96 (m, 1H), 1.91 (m, 2H), 1.43(s, 3H), 1.33 (m, 1H), 0.86 (m, 1H), 0.83 (d, J=7.1 Hz, 3H), 0.51 (d,J=8.1 Hz, 2H), 0.11 (m, 2H); IR (film) ν_(max) 2916, 1720, 1270 cm⁻¹; MS(CI) m/z 314 (M+H)⁺; Anal. calc. for C₂₀H₂₇NO₂: C, 76.64; H, 8.68; N,4.47. Found: C, 76.37; H, 8.93; N, 4.38.

(±)-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]-methanol[16]. Under a blanket of N₂ at 0° C.,(±)-3(cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxyhcacid methyl ester [3] (0.1062 g, 0.34 mmol), LiAlH₄ powder (0.0258 g,0.68 mmol) and dry THF (0.77 mL) were placed in a one-neck round bottomflask equipped with condenser and stir bar. The ice/water bath wasremoved and the reaction was stirred at reflux for 24 h. The mixture wascooled to 25° C. and quenched by adding water dropwise untileffervescence ceased. The mixture was then treated with 10% H₂SO₄ andstirred at 25° C. for 3 hours. The mixture then was extracted withdiethyl ether (2×) and the organic layer was dried (Na₂SO₄) and thesolvent was removed in vacuo. The crude product was purified by flashcolumn chromatography using CH₂Cl₂:MeOH/10:1 as eluent to provide thedesired product [16] (0.0557 g, 57%) as a light yellow oil: ¹H NMR (500MHz, CDCl₃) δ 7.24 (d, J=17 Hz, 1H), 7.10 (m, 1H), 7.08 (d, J=21.2 Hz,1H), 4.64 (s, 2H), 3.14 (m, 1H), 2.91 (d, J=18.5 Hz, 1H), 2.68 (m, 2H),2:47 (m, 1H), 2.31 (m, 1H), 1.92 (m, 6H), 1.34 (m, 3H), 0.84 (d, J=7.1Hz), 0.50 (m, 2H), 0.11 (m, 2H); Anal. calc. for C₁₉H₂₇NO: C, 79.95; H,9.53; N, 4.91. Found: C, 79.70; H, 9.50; N, 4.68.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-N-hydroxy-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamidine[14]. A modification of a known procedure (Jendralla, H.; Seuring, B.;Herchen, J.; Kulitzscher, B.; Wunner, J. Tetrahecron 1995, 51,12047-12068) was used in this preparation. A mixture of(±)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carbonitrile[1] (0.230 g, 0.82 mmol), hydroxylamine hydrochloride (0.100 g, 1.44mmol) and triethylamine (0.30 mL, 2.15 mmol) in 1 mL of absolute ethanolwas stirred at reflux under an argon atmosphere for 5 h. The reactionmixture was concentrated in vacuo and the residue was taken up in 15 mLof CH₂Cl₂ and washed with water. The organic phase was dried (Na₂SO₄)and evaporated to give crude product. Flash column chromatography usingCH₂Cl₂:MeOH:NH₄OH (conc)/25:1:0.1 provided the desired compound 14(0.216 g, 84%) as a white foam: ¹H NMR (500 MHz, CDCl₃) δ 9.48 (br s,1H), 7.56 (d, J=1.5 Hz, 1H), 7.33 (dd, J₁=1.5 Hz, J₂=7.8 Hz, 1H), 7.08(d, J=7.8 Hz, 1H), 4.84 (s, 2H), 3.19 (m, 1H), 2.94 (d, J=18.8 Hz, 1H),2.72 (m, 2H), 2.48 (dd, J=6.3 Hz, J₂=12.5 Hz, 1H), 2.34 (dd, J₁=6.6 Hz,J₂=12.5 Hz, 1H), 2.01 (m, 3H), 1.42 (s, 3H), 1.34 (d, J=11.4 Hz, 1H),0.92 (m, 1H), 0.84 (d, J=6.8 Hz, 3H), 0.51 (m, 2H), 0.12 (m, 2H); IR(film) ν_(max) 3365, 2921, 1634, 1577 cm⁻¹; MS (CI) m/z 314 (M+H)⁺;Anal. calc. for C₁₉H₂₇N₃O: C, 72.81; H, 8.68; N, 13.47. Found: C, 72.96;H, 8.67; N, 13.18.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-thiocarboxamide[5]. A modification of a known procedure (Varma R. S.; Kumar, D. OrganicLett. 1999, 1, 697-700) was used in this preparation. A mixture of(O)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamide[4] (0.0298 g, 0.1 mmol) and Lawsson's reagent (0.0320 g, 0.08 mmol) in1 mL of toluene was sealed in a glass tube under an argon atmosphere.The glass tube was put in a microwave oven and irradiated for 7 nmin.Additional Lawsson's reagent (0.0160 g, 0.04 mmol) was added and thereactants was allowed to be irradiated for additional 7 min. Thereaction mixture was taken up in 10 mL of CH₂Cl₂ and washed with water.The organic phase was dried with sodium sulfate and evaporated to givecrude product. Chromatography on silica gel using CH₂Cl₂:MeOH:NH₄OH(conc)/40:1:0.1 the provided desired compound 5 (0.022 g, 70.1%) as ayellow crystalline solid: mp 171-173° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.78(d, J=1.9 Hz, 1H), 7.64 (brs, 1H), 7.60(dd, J₁=1.9 Hz, J₂=8.1 Hz, 1H),7.19 (brs, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.16 (m, 1H), 2.95 (d, J=19.0Hz, 1H), 2.70 (m, 2H), 2.46 (dd, J₁=6.1 Hz, J₂=12.4 Hz, 1H), 2.32 (dd,J₁=6.3 Hz, J₂=12.4 Hz, 1H), 1.92 (m, 3H), 1.43 (s, 3H), 1.34 (m, 1H),0.85 (m, 1H), 0.83 (d, J=7.1 Hz, 3H), 0.51 (m, 2H), 0.10 (m, 2H); IR(film) ν_(max) 3172, 2920, 1617, 1424 cm⁻¹; MS (CI) m/z 315 (M+H)⁺;Anal. calc. for C₁₉H₂₆N₂S0.75H₂O: C, 69.58; H, 8.45; N, 8.54.

Found: C, 69.54; H. 8.15; N, 8.26.

(±)-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]-methylamine[15].(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carbonitrile[1] (0.154 g, 0.55 mmol) was dissolved in Et₂O (1.1 mL) to obtain a 0.5M solution. This solution was added dropwise via syringe to a vigorouslystirred solution of 1.0 M LiAlH₄ in Et₂O (1.1 mL, 1.1 mmol) at 0° C.After stirring at room temperature for 10 min, water was added dropwiseto quench the reaction. The resulting solution was then extracted withEtOAc several times and the combined EtOAc layers were dried (Na₂SO₄),and filtered. The solvent was removed in vacuo and the residue purifiedby flash column chromatography (CH₂Cl₂:MeOH:Et₃N/10:1:0.2) to yield thedesired product 15 (0.105 g, 67%) as a brown oil: ¹H NMR (500 MHz,CDCl₃) δ 7.16 (s, 1H), 7.04 (m, 2H), 3.82 (s, 2H), 3.16 (s, 1H), 2.91(d, J=8.3 Hz, 1H), 2.70 (m, 2H), 2.49 (m, 1H), 2.34 (m, 1H), 1.92 (m,5H), 1.39 (m, 4H), 0.85 (m, 4H), 0.51 (d, J=7.6 Hz, 2H), 0.11 (m, 2H);IR (film) ν_(max) 3075, 2962, 2917, 2814, 1574, 1499, 1462, 1428, 1380,1333, 1218, 1101, 1075, 1018, 963 cm⁻¹; Anal. calc. forC₁₉H₂₈N_(20.5)H₂O: C, 77.77; H, 9.96; N, 9.54. Found: C, 78.18; H,10.17; N, 9.39.

(±)-N-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]-formamide[19]. A modification of a known procedure (Chakrabarty, M.; Khasnobis,S.; Harigaya, Y.; Kinda, Y. Synthetic Comm. 2000, 30, 187-200.) was usedin this preparation.(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-amine[37] (0.091 g, 0.337 mmol) was treated with 96% formic acid (20 mL) andwas heated at 100° C. for 14 h. The solution was then poured ontocrushed ice and basified with solid NaHCO₃. The organic material wasextracted into EtOAc (3×) and the extracts were washed with water anddried (Na₂SO₄). After concentration in vacuo, the crude product waspurified by flash column chromatography (CH₂Cl₂:MeOH:NH₄OH/10:1:0.05) toyield the desired product 19 as a brown oil (0.065 g, 65%): ¹H N (500MHz, CDCl₃) δ 8.62 (d, J=11.5 Hz, 0.5H, CHO of one rotomer), 8.34 (d,J=1.7 Hz, 0.5H, CHO of other rotomer), 8.17 (d, J=10.5 Hz, 0.5H, NH ofone rotomer), 7.57 (br s, 0.5H, NH of other rotomer), 7.36 (m, 1H), 7.04(m, 1H), 6.89 (m, 1), 3.15 (m, 1H), 2.90 (m, 1H), 2.72 (m, 2H), 2.47 (m,1H), 2.32 (m, 1H), 1.95 (m, 3H), 1.32 (m, 4H), 0.85 (m, 4H), 0.51 (m,2H), 0.11 (m, 2H); IR (film) ν_(max) 3265, 2963, 2922, 1694, 1682, 1614,1538, 1503, 1462, 1402, 1380, 1311, 1218, 1100, 1074, 1020, 964, 888,808 cm⁻¹; MS (CI) m/z 299 (M+H)⁺; Anal. calc. for C₁₉H₂₆N₂O 0.125H₂O: C,75.90; H, 8.88; N, 9.32. Found: C, 76.00; H, 8.95; N, 9.13.

The remaining compounds of Table 1 were prepared in similar fashion,except Example 8, which was made by the CO/palladium route, but with aslight variation using 2.0 M CH₃NH₂ in THF, rather than gaseous CH₃NH₂,and DMF rather than DMSO; mp=155-156° C.; 25.6% yield. 24-[the(±)-8-CONH₂ analogue of ethylketocyclazocine (R² and R^(2a)=O; R⁶=Et)]was made by the nitrile hydrolysis route, mp=194-196° C.; Step 1-89.1%,Step 2-81.4%. 23-[the (±)-8-CONH₂ analogue of ketocyclazocine (R² andR^(2a)=O; R⁶=Me)] was made by the nitrile hydrolysis route, mp=206-207°C.; Step 1-99.7%, Step 2-94.2%. It was also made by the CO/Pd route in34.7% yield.

In general, the chemistry described above works in the presence of thevariety of functional groups found on known core structures. Theexceptions would be morphine and congeners having a free 6-OH, which canbe protected by a TBDPS (t-butyldiphenylsilyl) group [see Wentland et alJ. Med. Chem. 43, 3558-3565 (2000)].

The compound identified as Example 43 in table 4 was prepared bytreating the nitrile of nalbuphine with an excess of potassium hydroxidein t-butanol as described for example 4 above. Hydrolysis of the nitrileappears to have proceeded more slowly than elimination and ring opening.

Although this invention is susceptible to embodiment in many differentforms, preferred embodiments of the invention have been shown. It shouldbe understood, however, that the present disclosure is to be consideredas an exemplification of the principles of this invention and is notintended to limit the invention to the embodiments illustrated. It maybe found upon examination that certain members of the claimed genus arenot patentable to the inventors in this application. In this event,subsequent exclusions of species from the compass of applicants' claimsare to be considered artifacts of patent prosecution and not reflectiveof the inventors' concept or description of their invention; theinvention encompasses all of the members of the genus (I) that are notalready in the possession of the public.

1-22. (canceled)
 23. A method for preparing a second compound thatinteracts with an opioid receptor when a first compound that interactswith an opioid receptor is known, said first compound containing aphenolic hydroxyl, said method comprising converting said phenolichydroxyl to a residue chosen from the group consisting of —CONH₂,—C(═S)NH₂, —C(O)NHOH, —NHCHO, and —NHCHS wherein said first compoundcontaining a phenolic hydroxyl is of the formula:

wherein R is chosen from the group consisting of CH₃ (registry number:69926-34-7): CH₂CH₂CH(OH)C₆H, ₁ (Registry Number: 119193-09-8):CH₂CH(CH₂Ph)CONHCH₂CO₂H (Registry Number: 156130-44-8); (CH₂)₃CH(CH₃)₂(Registry Number: 151022-07-0): and (CH₂)₃-2-thienyl (Registry Number:149710-80-5).
 24. A method according to claim 23 wherein said phenolichydroxyl is converted to a carboxamide, a formamide, a hydroxyamidine ora thioamide.
 25. (canceled)
 26. A method for decreasing the rate ofmetabolism of a compound that interacts at an opioid receptor, saidcompound containing a phenolic hydroxyl, said method comprisingconverting said phenolic hydroxyl to a residue chosen from the groupconsisting of —CONH₂, —C(═S)NH₂, —C(O)NHOH, —C(═NOH)NH₂, —NHCHO, and—NHCHS wherein said compound containine a phenolic hydroxyl is of theformula:

wherein R is chosen from the group consisting of CH₃ (Reeistrv Number:69926-34-7); CH₂CH₂CH(OH)C₆H₁₁ (Registry Number: 119193-09-8);CH₂CH(CH₂Ph)CONHCH₂CO₂H (Registry Number: 156130-44-8); (CH₂)₃CH(CH₃)₂(Registry Number: 151022-07-0); and (CH₂)₃-2-thienyl (Registry Number:149710-80-5).
 27. A method according to claim 26 said phenolic hydroxylto a carboxamide, a formamide, a hydroxyamidine or a thioamide 28-50.(canceled)
 51. A compound of formula

wherein A is chosen from the group consisting of: —CONH₂, —C(═S)NH₂,—C(O)NHOH, and —NHCHO; and R is chosen from the group consisting of—CH₃, —CH₂CH₂CH(OH)C₆H₁₁, —CH₂CH(CH₂Ph)CONHCH₂CO₂H, —(CH₂)₃CH(CH₃)₂ and—(CH₂)₃-2-thienyl.
 52. A compound according to claim 51 wherein A is—C(═S)NH₂.
 53. A compound according to claim 51 wherein A is —C(O)NHOH.54. A compound according to claim 51 wherein A is —NHCHO.
 55. A compoundaccording to claim 51 wherein A is —CONH₂.
 56. A compound according toclaim 55 wherein R is —CH₃.
 57. A compound according to claim 55 whereinR is —(CH₂)₃-2-thienyl.
 58. A compound according to claim 55 wherein Ris —CH₂CH(CH₂Ph)CONHCH₂CO₂H.
 59. A compound according to claim 58 offormula


60. A compound according to claim 55 wherein R is —(CH₂)₃CH(CH₃)₂.
 61. Acompound according to claim 55 wherein R is —CH₂CH₂CH(OH)C₆H₁₁.
 62. Acompound according to claim 61 of formula